Rhenium-Oxo Catalysts

Aldrich ChemFiles 2006, 6.1, 3.

Rhenium(V) forms a large number of stable octahedral complexes with multiple bonds to oxygen with traditional Re systems focusing on formal, stoichiometric oxygen atom transfer to organic reductants such as phosphines, alkenes, and sulfides.1 Re-catalyzed methodologies remained largely unexplored as a means of converting simple organic compounds to functionalized intermediates well suited for use in total synthesis. Recently, the Toste research group at Berkeley has used high oxidation-state Re complexes in a variety of organic transformations (Scheme 1).2 Re‑oxo complexes offer several powerful advantages in metal-mediated catalysis, including 1) the high oxidation-state of the metal offers inherent stability against moisture deactivating the catalyst, and 2) in most reaction paradigms, the mild conditions allow for the activation of substrates that contain sensitive functional groups. We are pleased to offer two Re-oxo complexes that have been shown to facilitate C–C, C–O, and C–N bond forming reactions under mild conditions, without exclusion of moisture.

Scheme 1.

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[Re(O)Cl3(SMe2)(Ph3PO)] (1)

The first Re catalyst performs effortlessly in the metal-mediated addition reaction of nucleophiles to oleosaccharides (Scheme 2).3 The O-glycosylation reaction of nucleophiles to glycals proceeded well in a variety of solvents; however, non-polar solvents served as the optimal media. A diverse array of glycosyl donors and acceptors (i.e., olefins) were utilized and the Re(V)-oxo complex tolerated a multitude of protecting groups, including acetals, silyl ethers, acetates, and benzoates. The mild nature of the Re-catalyst system allows an iterative approach to the synthesis of trisaccharides via the successive coupling of two glycals followed by the reaction of the newly formed 2-deoxysaccharide with a thio-glycosyl acceptor. Interestingly, the catalytic addition of simple thiols, such as thiophenol to galactals, resulted in good yields of 2-thioglycosides with no observable catalyst poisoning. It should also be noted that this simple Re(V) complex acts as a convenient precursor to chiral Recatalysts via ligand metathesis (Scheme 3).4

Scheme 2.

Scheme 3.

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[(dppm)Re(O)Cl3] (2)

dppm = bis(diphenylphosphino)methane

The second Re complex 2, based upon a strongly binding bidentate phosphine ligand, catalyzes the coupling of propargylic alcohols and allyl silanes to afford 1,5-enynes (Scheme 4).2b Toste and co-workers have prepared a wide variety of 1,5-enynes by the metal-catalyzed formation of propargylic sp3–sp3 carbon–carbon bonds (Table 1). This methodology exhibits high yields of enynes at low catalyst loadings (1–5 mol %) and temperatures (rt to 65 °C). Addition of a catalytic (5 mol %) amount of ammonium hexafluorophosphate completely suppresses competing rearrangements to enone byproducts. The reaction proceeds without complications in the presence of electron‑rich and electron-poor substrates and sterically demanding ortho-disubstituted-phenyl groups present no impediment to enyne formation.

Scheme 4.

Table 1.

The broad utility of this rhenium catalyst extends through reactions that contain non-benzylic propargyl alcohols, however, silver hexafluoroantimonate must be used as the co-catalyst. It is worth noting that the Re(V) catalyst can be recovered and reused in many cases, without observable decreases in catalyst activity.

The Toste group also varied the nature of the allylsilane source to include enantioenriched materials (Scheme 5). The Re-catalyzed coupling of crotylsilane 3 consistently yielded the propargyl adduct as a 1.2:1 mixture of diastereomers without erosion of the initial enantiopurity. The propargyl coupling reaction exhibits higher diastereoselectivities if large groups (i.e., Me) are present in the ortho position of the allyl silane.

Scheme 5.

Additional reactivity of rhenium catalyst 2 has been explored in the propargylic etherification reaction of benzylic and non-benzylic propargyl alcohols (Scheme 6).2a Primary, secondary, and tertiary alcohols all perform as nucleophiles in the etherification, but with diminished yields of the ether adduct in the case of tert-butyl alcohol. In highly polar solvents, the substitution reaction proceeded well with low catalyst loadings under ambient conditions at 65 °C. Most importantly, the etherification process is not accompanied by oxidation and rearrangement reactions, due to the mild nature of the Re catalyst.

Scheme 6.

Variation in the propargyl alcohol phenyl substitution is well tolerated and notably acid-labile groups, such as ketals, acetals, and t-butylcarbamates, were not cleaved under the reaction conditions. Furthermore, the propargylic etherification runs smoothly in the presence of aryl–bromine bonds and pendant alkenyl groups were tolerated.

The mild Re(V) catalyst has been applied to reactions of numerous aromatic substrates with propargyl alcohols.2c This methodology offers a practical, direct route for the fabrication of propargylic arenes via aryl and heteroaryl C–H bond activation. 5 mol % of potassium hexafluorophosphate is required to ensure high yields of the coupled product, presumably by abstracting a chloride ligand from the Re complex and accelerating alcohol binding. The propargylation of phenols, which usually results in competitive O-alkylation and benzopyran formation, progresses cleanly to yield complex organic molecules such as mimosifoliol.5 It is worth noting that the reaction is completely selective for formation of the propargyl adduct, even when the alkyne is substituted with 1,1-disubstituted olefins that are susceptible to electrophilic attack (Scheme 7).

Scheme 7.

Mild lab-bench conditions for the reactions of propargyl alcohols with sulfonamides and carbamates have also recently been reported by the Toste group.2d The broad scope, ease of reaction handling, and facile construction of C–N bonds in a catalytic fashion make this methodology a valuable tool for synthetic chemists. This reaction is comprised of a broad spectrum of carbamates, alkynyl species, and phenyl/aryl reaction partners including synthetically versatile silyl and halide substituted organic building blocks. The successful development of this chemistry has fueled the expedient synthesis of pentabromopseudilin (Scheme 8), which is known as a potent lipoxygenase inhibitor.6

Scheme 8.

The Re(V) catalysts featured above represent powerful tools for the practical construction of C–C, C–O, and C–N bonds under mild conditions, as exemplified in the vast array of architectures accessed by this methodology.

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  1. Rouschias, G. Chem. Rev. 1974, 74, 531-566.
  2. (a) Toste, F. D. et al. J. Am. Chem. Soc. 2003, 125, 6076. (b) Toste, F. D. et al. J. Am. Chem. Soc. 2003, 125, 15760. (c) Toste, F. D. et al. Org. Lett. 2004, 6, 1325. (d) Toste, F. D. et al. Org. Lett. 2005, 7, 2501.
  3. Toste, F. D. et al. J. Am. Chem. Soc. 2004, 126, 4510.
  4. Toste, F. D. et al. J. Am. Chem. Soc. 2005, 127, 12462 and references therein.
  5. (a) Wall, M. E. et al. J. Nat. Prod. 1996, 59, 190. (b) Pettus, T. R. R. Synlett 2003, 2234.
  6. Holman, T. R. et al. J. Med. Chem. 2004, 47, 4060.

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